This invention relates to compounds for treatment and detection of hyperproliferatve tissues such as tumors using photodynamic methods. These compounds have the ability to preferentially collect in such tissues when injected into an organism and absorb light either to cause reduction in growth of the tissue, such as by its destruction, or to cause emission of energy from the tissue that can be detected to locate the tissue. Such reduction and detection using photodynamic compounds is collectively referred to herein as photodynamic therapy.
Photodynamic therapy (PDT) is a relatively new modality for the treatment of various types of solid tumors. Many porphyrins and related photosensitive compounds demonstrate the ability to selectively accumulate in neoplastic tissue after intravenous injection and sensitize the tissue to photoirradiation. Activation of the photosensitive agent by visible light, delivered by a laser through fiber optics, results in the generation of cytotoxic agents. It is currently accepted that the production of singlet oxygen, formed from molecular oxygen, formed from molecular oxygen by the transfer of energy directly or indirectly from the activated photosensitizer, is responsible for tumor homeostasis and the observed tumor destruction.
Following absorption of light, the photosensitizer is transformed from its ground singlet state (P) into an electronically excited triplet state (3P*; xcfx84xcx9c10xe2x88x922 sec.) via a short-lived excited singlet state (1P*; xcfx84xcx9c10xe2x88x926 sec.) The excited triplet can undergo non-radiative decay or participate in an electron transfer process with biological substrates to form radicals and radical ions, which can produce singlet oxygen and superoxide (O2xe2x88x92) after interaction with molecular oxygen (O2). Singlet oxygen is the key agent responsible for cellular and tissue damage in PDT, causing oxidation of the target tissue (T); there also is evidence that superoxide ion may be involved.
In 1978, it was reported that a combination of hematoporphyrin derivative (HpD) and light was effective in causing partial or complete tumor necrosis in 111 of 113 tumors in 25 patients. PDT with Photofrin(copyright), a purified HpD, has been approved in Canada for bladder and esophageal cancer; in the Netherlands and France for early and advanced stage esophageal cancer; in Japan for early stage lung, esophageal, gastric, and cervical cancer; and in the United States for advanced stage esophageal and lung cancers. More than 10,000 patients worldwide have been treated with PDT for a multiplicity of tumors accessible to light, including skin, lung, bladder, head and neck, breast, and esophageal cancers. Photofrin(copyright), the current commercially used photosensitive drug, has some desirable characteristics, including good efficacy, water solubility, good yield of singlet oxygen, and ease of manufacture. However, Photofrin(copyright) has some disadvantageous properties: (i) it is a complex mixture of porphyrin dimers and higher oligomers linked by ether, ester, and/or carbon-carbon bonds and, therefore is difficult to study; (ii) it shows skin phototoxicity in patients for four to six weeks after administration; (iii) due to its relatively weak absorbance in the red region (630 nm), lack of penetration of light through tissue limits current clinical applications of Photofrin(copyright) in PDT to the destruction of cancerous tissue less than 4 mm from the source of light used in the therapy.
It has been established that both absorption and scattering of light by tissue increase as the wavelength decreases. Therefore, tissue penetration increases as the wavelength increases. Heme proteins in tissue account for most of the absorption of light in the visible region, and in tissue, light penetration drops off rapidly below 550 nm. However, there is a significant increase in penetration from 550 to 630 nm, and penetration doubles again to 700 nm. This is followed by a 10% increase in tissue penetration as the wavelength moves towards 800 nm.
Another reason that sets the ideal wavelength to 700-800 nm is the availability of the light sources in this region. Currently available laser lights used at 630 nm are expensive and not easy to handle clinically. A better solution is to use diode lasers. Advantages of diode lasers are low cost, negligible running cost, high reliability, small size and portability. Although diode lasers are now becoming available at 630 nm, photosensitizers with absorption between 700 to 800 nm in conduction with diode lasers are still desirable for treating tumors that are deeply seated. All these factors establish 700 to more than 800 nm as the optimal wavelength absorption for an efficient photosensitizer. Besides the properties discussed previously, the preferential tumor localization, stability, singlet oxygen producing efficiency, stability, low toxicity and solubility in appropriate injectable solvents are other important factors to be considered in developing an effective PDT agent.
In recent years, a number of long wavelength ( greater than 650 nm) absorbing photosensitizers have been reported as potential candidates for achieving maximum tissue penetration. Among such compounds, some naturally occurring bacteriochlorophylls have been reported as effective photosensitizers in preliminary in vitro and in vivo studies. However, most of the naturally occurring bacteriochlorins which have absorptions at 760-780 nm are extremely sensitive to oxidation, which results in a rapid transformation into the chlorin state which has an absorption maximum at or below 660 nm (see FIG. 1). Furthermore, if a laser is used to excite the bacteriochlorin in vivo, oxidation may result in the formation of a new chromophore absorbing outside the laser window, which reduces the photosensitizing efficacy. In order to render PDT more generally applicable to tumor therapy, there is need for long wavelength absorbing photosensitizers, such as, stable bacteriochlorins, which should also be able to localize in relatively high concentration at the tumor site related to normal tissues.
It is therefore an object of the invention to develop a stable photosensitizer that preferentially absorbs into hyperproliferative tissue and absorbs light efficiently at a wavelength of from about 700 to about 850 nm.
It is a further object of the invention to provide a method for photodynamic therapy using such stable photosensitizers.